Electronic Supplementary Information for Monatshefte für Chemie
Tetraethylammonium 2-(carbamoyl)benzoate as an Efficient Organocatalyst for One-pot
Synthesis of Hantzsch 1,4-Dihydropyridine and Polyhydroquinoline Derivatives
Mahsa Yarhosseini, Shahrzad Javanshir*, Mohammad G. Dekamin, Mohammad Farhadnia
Contents
1.
Page
Experimental section
2
1.1.
Instruments and characterization
2
1.2.
1.3.
General procedure for preparation of tetraethylammonium 2-(carbamoyl)benzoate (TEACB) (1)
Chemical characterization of TEACB (1)
2
2
1.4.
General procedure for the synthesis of 1,4-DHPs derivatives (5a-q) catalyzed by TEACB
3
1.5.
General procedure for the synthesis of polyhydroquinoline derivatives (7a-p and 8a-q) catalyzed by
TEACB
3
Chemical characterization of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3carboxylate (8e)
5-7
Chemical characterization of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8i)
7-10
Chemical characterization of 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic
acid ethyl ester (7f)
10-13
Chemical characterization of Ethyl 4-(2,4-dichlorophenyl)-2-methyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-3carboxylate (7n)
13-15
Chemical characterization of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate (5e)
15-18
Chemical characterization of Diethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q)
19-21
1
1.
Experimental section
1.1.
Instruments and characterization
All chemicals were purchased from Merck, Fluka and Sigma-Aldrich companies and were used without further
purification, except for benzaldehyde, which was used as a fresh distilled sample. Analytical thin layer
chromatography (TLC) for monitoring reactions was performed using Merck 0.2 mm silica gel 60 F-254 Al-plates
using ethyl acetate and n-hexane as eluents. Melting points were determined in open capillaries using an
Electrothermal 9100 instrument. Infrared (IR) spectra were acquired on a Shimadzu FT-IR-8400S spectrometer. 1H
NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded on a Bruker DRX-500 Avance spectrometers with
CDCl3 as solvent at ambient temperature and tetramethylsilane (TMS) as the internal standard. All chemical shifts are
given relative to TMS. All yields refer to the isolated products.
1.2.
General procedure for preparation of tetraethylammonium 2-(carbamoyl)benzoate (TEACB) (1)
To a 25 mL round-bottomed flask equipped with a magnetic stirrer and a condenser were added phthalimide (6.80
mmol, 1.00 g) and tetraethylammonium hydroxide (6.80 mmol, 20% w/w in water, d = 1.01 g/mL, 5.0 mL). The
mixture was stirred at room temperature for 5 min. To this was added 5 mL of distilled water and the mixture was
refluxed for 4 h and then allowed to cool. The solvent was evaporated and the residue was kept at 0–4 °C for 1 hour
to afford pure TEACB in quantitative yield. The white crystals were collected and dried under reduced pressure.
1.3.
Chemical characterization of TEACB (1)
White crystals, Mp 86–88 °C; IR (KBr) cm-1: 3561–3208 (br s, N–H), 3067, 2988, 2953, 1666, 1580, 1550, 1487,
1400, 1173, 1002, 1H NMR (500 MHz, CDCl3) δ(ppm): 0.98–1.01 (t, J = 7.20 Hz, 12H), 2.97–3.01 (t, J = 7.20 Hz,
8H), 6.15 (br s, s, 1H), 7.05–7.08 (t, J = 7.50 Hz, 1H), 7.16–7.19 (t, J = 7.40 Hz, 1H), 7.34–7.36 (d, J = 7.50 Hz, 1H),
7.70–7.72 (d, J = 7.75 Hz, 1H), 10.05 (br s, s, 1H), 13C NMR (125 MHz, CDCl3) δ(ppm): 7.6, 52.4, 126.7, 128.3,
128.4, 129.6, 130.6, 143.5, 170.8, 174.9, Anal. Calcd for C1 6H26N2O3: C, 65.28; H, 8.90; N, 9.52. Found: C, 65.02;
H, 8.75; N, 9.82.
Fig. 1 FT-IR spectrum of TEACB (1)
2
Fig. 2 1H NMR spectrum of TEACB (1) in CDCl3
Fig. 3 1H NMR spectrum of TEACB (1) in CDCl3 (Expanded aliphatic and aromatic region).
3
Fig. 4
13
C NMR spectrum of TEACB (1)
1.4. General procedure for the synthesis of 1,4-DHPs derivatives (4a-q) catalyzed by TEACB
A mixture of aldehyde (1 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate (1.5 mmol) and TEACB
(%10mol) in 2ml absolute ethanol was heated at 80°C for the time indicated in table 2 into a 10 mL round bottomed
flask equipped with a magnetic stirrer until products were formed completely. The reaction progress was monitored
by TLC. After completion of the reaction the solvent was evaporated under vacuum to furnish a solid which was
recrystallized from ethyl acetate-hexane.
1.5. General procedure for the synthesis of polyhydroquinoline derivatives (6a-p and 7a-q) catalyzed by
TEACB
A mixture of aldehyde (1 mmol), ethyl acetoacetate (1mmol), dimedone/1.3-cyclohexanedione (1 mmol) and
ammonium acetate (1.5 mmol) and TEACB (%10mol) in 2ml absolute ethanol was heated at 80°C for the time
indicated in table 3 into a 10 mL round bottomed flask equipped with a magnetic stirrer until products were formed
completely. The reaction progress was monitored by TLC. After completion of the reaction the solvent was evaporated
under vacuum to furnish a solid which was recrystallized from ethyl acetate-hexane.
Chemical characterization of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3carboxylate (8e)
Yellowish white crystals, mp 223 °C, yield: 96%, IR (KBr) cm-1: 3336, 3097, 2923, 1699, 1651, 1487, 1434, 1305,
1213, 1184, 1099, 1018, 845, 750, 1H NMR (300 MHz, DMSO-d6): δ (ppm): 0.95 (s, 3H), 1.03 (s, 3H), 1.19 (t, 3H,
J=7.2, OCH2CH3), 2.04-2.46 (m, 7H), 4.07 (q, 2H, J=7.2, OCH2CH3), 5.17 (s, 1H), 6.66 (s, 1H), 6.81–6.8 (m, 2H),
7.17-7.19 (m, 2H), 9.27 (s, 1H, NH).
4
Fig. 5 FTIR spectrum of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8e).
Fig. 6 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8e)
in DMSO-d6.
5
Fig. 7 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8e)
in DMSO-d6 (Expanded aliphatic region)
Fig. 8 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8e)
in DMSO-d6 (Expanded aliphatic region).
6
Fig. 9 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8e)
in DMSO-d6 (Expanded aromatic region).
Chemical characterization of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8i)
Yellowish white crystals, mp 268270 °C, yield: 94%, IR (KBr) cm-1: 3224, 3078, 2958, 1701, 1606, 1490, 1380,
1309, 1280, 1217, 1107, 1072, 1029, 850, 738, 532, 1H NMR (300 MHz, CDCl3 & DMSO-d6): δ (ppm): 0.96 (s, 3H),
1.07 (s, 3H), 1.22 (t, 3H, J=7.2 Hz, OCH2CH3), 2.19-2.36 (m, 4H), 2.25 (s, 3H), 2.36 (s, 3H), 4.03-4.10 (q,2H, J=7.2
Hz), 5.01 (s, 1H), 7.00 (d, 2H, J=7.5 Hz), 7.18 (d, 2H, J=7.8 Hz).
7
Fig. 10 FTIR spectrum of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(8i).
Fig. 11 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8i)
in CDCl3 & DMSO-d6.
8
O
O
O
N
H
Fig. 12 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8i)
in CDCl3 & DMSO-d6 (Expanded aliphatic region).
Fig. 13 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8i)
in CDCl3 & DMSO-d6 (Expanded aliphatic region).
9
Fig. 14 1H NMR spectrum of Ethyl 2,7,7-trimethyl-5-p-tolyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (8i)
in CDCl3 & DMSO-d6 (Expanded aromatic region).
Chemical
characterization
carboxylic acid ethyl ester (7f)
of
2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-
Yellowish white crystals, mp 232-234°C, yield: 95%, IR (KBr) cm-1: 3290, 3210, 3072, 2935, 1679, 1608, 1483,
1377, 1224, 1182, 1134, 1080, 838, 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.14 (t, 3H, J=6.9 Hz, OCH2CH3), 1.74–
2.51 (m, 6H, 3×CH2), 3.38 (s, 3H), 3.98 (q, 2H, J=6.9 Hz, OCH2CH3), 4.79 (s, 1H), 6.57 (d, 2H, J=8.1 Hz, Ar-H),
6.93 (d, 2H, J=8.1 Hz, Ar-H), 9.09 (s, 2H, NH, OH).
10
Fig.15 FTIR spectrum of 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (7f).
Fig. 16 1H NMR spectrum of 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (7f)
11
In DMSO-d6
Fig. 17 1H NMR spectrum of 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (7f)
in DMSO-d6 (Expanded aliphatic region).
Fig. 18 1H NMR spectrum of 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (7f)
in DMSO-d6 (Expanded aliphatic region).
12
Fig. 19 1H NMR spectrum of 2-Methyl-5-oxo-4-(4-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (7f)
in DMSO-d6 (Expanded aromatic region).
Chemical characterization of Ethyl 4-(2,4-dichlorophenyl)-2-methyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-3carboxylate (7n)
Off-white solid, mp 249 °C, yield: 92%, IR (KBr) cm-1: 3286, 3068, 2945, 1695, 16206, 1477, 1379, 1222, 1182,
1137, 1072, 975, 700, 1H NMR (300 MHz, DMSO-d6) δ (ppm): 0.65-1.11 (t, 3H, J=7.2 Hz), 1.61 (m, 1H), 1. 88 (m,
1H), 2.13–2.19 (m, 3H), 2.47–2.51 (m, 4H), 3.93-3.97 (q, 2H, J=7.2 Hz,), 5.17 (s, 1H), 7.35 (m, 1H), 7.28 (m, 2H),
9.23 (brs, 1H, NH).
13
Fig.20 FTIR spectrum of Ethyl 4-(2,4-dichlorophenyl)-2-methyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-3-carboxylate (7n).
14
Fig. 21 1H NMR spectrum of Ethyl 4-(2,4-dichlorophenyl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (7n)
in DMSO-d6.
Fig.22 1H NMR spectrum of Ethyl 4-(2,4-dichlorophenyl)-2-methyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-3-carboxylate (7n)
in DMSO-d6 (Expanded aliphatic region).
Chemical characterization of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate
(5e)
Yellowish white crystals, mp 170°C, yield: 96%, IR (KBr) cm-1: 3344, 3099, 2925, 2853, 1693, 1655, 1487, 1369,
1300, 1211, 1128, 1093, 854, 721, 1H NMR (250 MHz, CDCl3): δ (ppm): 1.29 (t, J=7.25, 6H), 2.36 (s, 6H), 4.20 (q,
J=7.25, 4H), 5.36 (s, 1H), 5.77 (s, 1H), 6.80–6.88 (m, 1H), 7.06–7.08 (dd, 1H), 7.28 (s, 1H)
15
Fig. 23 FTIR spectrum of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate (5e)
Fig. 24 1H NMR spectrum of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate (5e) in CDCl3
16
Fig. 25 1H NMR spectrum of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate (5e) in CDCl3
(Expanded aliphatic region)
Fig. 26 1H NMR spectrum of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate (5e) in CDCl3
(Expanded aliphatic region)
17
Fig. 27 1H NMR spectrum of Diethyl 1,4-dihydro-2,6-dimethyl-4-(thiophen-2-yl)pyridine-3,5-dicarboxylate (5e) in CDCl3
(Expanded aromatic region)
18
Chemical characterization of Ddiethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q)
Yellow crystals, mp 147 °C, yield: 95%, IR (KBr) cm-1: 3432, 3336, 3244, 3097, 2980, 2320, 1690, 1645, 1491, 1446,
1373, 1327, 1298, 1220, 1120, 749, 1H NMR (250 MHz, CDCl3) δ (ppm): 1.31 (s, J=7 Hz, 6H), 2.35 (s, 6H), 4.23 (m,
J=7 Hz, 4H), 4.64 (d, 1H), 5.62 (s, 1H), 6.17 (dd, 1H), 6.23 (d, 1H), 7.17–7.36 (m, 5H).
Fig. 28 FT-IR spectrum of Diethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q)
19
Fig. 29 1H NMR spectrum of Diethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q) in CDCl3
Fig.30 1H NMR spectrum of Diethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q) in CDCl3
(Expanded aliphatic region)
20
Fig. 31 1H NMR spectrum of Diethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q) in CDCl3
(Expanded aliphatic region)
Fig. 32 1H NMR spectrum of Diethyl 2,6-dimethyl-4-styrylpyridine-1,4-dihydro-3,5-dicarboxylate (5q) in CDCl3
(Expanded aromatic region)
21